The principal objectives of this project are to identify improved therapeutic options for patients with CML. Imatinib mesylate (Gleevec, STI571) has significant activity in CML, but with standard-dose imatinib few patients have achieved a molecular remission. Thus the potential for cure with imatinib alone is questionable. The first aim is to determine whether pegylated interferon and GM-CSF in combination with high-dose imatinib may improve the molecular responses to high-dose imatinib alone. Patients with newly diagnosed CML will be treated with high-dose imatinib. After 6 months, they will be randomized to continue imatinib alone or in combination with PEG-IFN and GM-CSF. The goal is to improve the rate of molecular remissions at 12 months. The second aim of this project is to evaluate the significance of these molecular remissions. Patients will be monitored with competitive or real-time PCR during therapy. The objective is to determine whether complete molecular remission translate in long-term disease free survival. In addition, we will investigate whether the ratio of Bcr/Abl to Abl can be used to predict probabilyt of relapse, whether low levels below a certain threshold will identify a low probability of relapse and whether these could help determine duration of therapy, and whether increasing levels correlate with relapse and can thus be used to change treatment strategies. The third aim is to investigate whether immunotherapy, in the form of PR1 vaccine, can improve the responses in patients who are refractory to imatinib. Because PR1 is presented in an HLA-A2-restrivcted fashion, patients with this phenotype will be randomized to receive PR1 and imatinib, with or without interferon. The fourth aim is to investigate new agents for the treatment of CML refractory to imatinib. The first agent to be investigated is the proteasome inhibitor PS-341 or bortezomib. Patients will be treated with PS-341 twice weekly for 2 weeks every 3 weeks. Besides the clinical efficacy, the induction of apoptosis and the effect on CML cell cultures will be determined. This drug could eventually be combined with imatinib. Other new agents would eventually be used in this setting in subsequent years of this proposal. The long-term goal of this project is to improve the treatment of CML with the objective of achieving cures outside of the bone marrow transplant setting in a significant number of patients.